GENECARD-Gene Identification in Early-Onset CAD

描述（由申请人提供）：冠状动脉疾病是美国唯一的主要死亡原因。冠状动脉疾病（CAD）也是导致残疾的主要原因。识别增加CAD易感性的基因将对公共卫生产生深远的影响，从增强易感个体改变行为和生活方式的动机到提供有关CAD发展和治疗的基本生物学和临床信息。CAD是一种复杂的疾病，具有明确的遗传和环境危险因素。早发性冠状动脉疾病（EOCAD），定义为发病年龄小于50岁，已知具有特别强的遗传成分。然而，导致这种风险增加的实际基因和对CAD的基本理解仍然模糊不清。我们的目标是在男性50岁或女性55岁之前至少有两名成员患有心肌梗死、外科手术或功能检查确定的EOCAD的核心家庭的大样本中确定增加早发性冠状动脉疾病易感性的基因。我们使用GENECARD研究收集的438个家庭的395个微卫星标记完成了EOCAD的基因组筛选，GENECARD研究是一项涉及6个临床研究站点、葛兰素史克公司和杜克大学人类遗传学中心的合作研究。我们已经确定了9个地区，提供了这些家庭之间联系的一致证据。我们将集中研究包含染色体3q13-q22的区域，为连锁提供强有力和一致的证据（MLS=2.3）。我们建议对这些区域的原始家庭和另外近400个家庭的微卫星标记进行后续基因分型。这些区域的候选基因以及其他项目中从表达分析中鉴定出的基因将使用连锁和基于家族的关联进行分析。生物信息学分析和工具将有助于我们为后续研究鉴定新的标记物、snp和候选基因。我们坚信，对遗传因素和基因-环境相互作用的详细研究是确定有针对性的预防战略和更有效治疗的必要步骤。

DESCRIPTION (provided by applicant): Coronary artery disease is the single leading cause of death in the US. Coronary Artery disease (CAD) is also a leading cause of disability. Identification of genes increasing susceptibility to CAD would have far reaching public health impact from enhancing motivation to make behavioral and lifestyle changes in susceptible individuals to providing basic biological and clinical information about the development and treatment of CAD. CAD is a complex disease with clear genetic and environmental risk factors. Early onset (premature) coronary artery disease (EOCAD), defined as age of onset less than 50 years of age, is known to have a particularly strong genetic component. However the actual genes leading to this increased risk and to a basic understanding of CAD remain obscure. Our goal is to identify genes increasing susceptibility to early onset coronary disease in a large sample of nuclear families with at least two members with EOCAD defined on the basis of a myocardial infarction, surgical procedure, or functional test before the age of 50 in men or 55 in women. We have completed a genome screen for EOCAD using 395 microsatellite markers in 438 families collected by the GENECARD study, a collaborative study involving 6 clinical investigative sites, GlaxoSmithKline and the Duke Center for Human Genetics. We have identified 9 regions providing consistent evidence for linkage in these families. We will concentrate on a region encompassing chromosome 3q13-q22 providing strong and consistent evidence for linkage (MLS=2.3). We propose to perform follow-up genotyping of microsatellite markers in these regions in the original set of families and in an additional set of almost 400 families. Candidate genes in those regions as well as genes identified from expression analyses carried out in other projects will be analyzed using linkage and family-based association. Our efforts in identifying new markers, SNPs and candidate genes for the follow-up studies will be aided by bioinformatics analyses and tools. We strongly believe that a detailed study of genetic factors and gene-environment interactions is an essential step to identifying targeted preventive strategies and more effective treatments.